PROJECT SUMMARY ABSTRACT Learning disabilities are the most common behavioral deficit observed in children with Fetal Alcohol Spectrum Disorder (FASD). Currently, there are no established rationally-based clinically-effective pharmacotherapeutic interventions for these and related behavioral deficits. However, using a well-established rat model of FASD, we have observed that the histamine H3 receptor inverse agonist ABT-239 ameliorates prenatal alcohol exposure (PAE)-induced deficits in dentate gyrus long-term potentiation (LTP) and retention of memory. We have also observed increased H3 receptor-effector coupling and a heightened H3 receptor-mediated inhibition of glutamate release in the dentate gyrus of PAE rats. Our results suggest that PAE increases H3 receptor-mediated inhibition of glutamate release and that ABT-239 reduces this heightened inhibitory influence. These observations provide preclinical rationale for examining the efficacy of H3 receptor inverse agonists on treating learning and memory deficits in children with FASD. The working hypothesis for the preclinical UH2 phase of this proposal is that SAR152954, another histamine H3 receptor inverse agonist, will ameliorate PAE-induced behavioral and synaptic plasticity deficits by reversing PAE-induced decreases in activity-dependent potentiation of glutamate release. We will first examine the effects of four different doses of SAR152954 on PAE-induced deficits in one- trial contextual fear conditioning (Aim 1A) and the retention of spatial memory using the Morris Water Maze (Aim 1B), two behaviors quite sensitive to PAE-induced functional damage of the dentate gyrus. The milestone objective of Aim 1 will be to identify the optimal test dose (OTD) of SAR152954 that reverses PAE-induced memory deficits. Subsequently, we will examine whether the OTD dose of SAR152954 reverses PAE-induced deficits in dentate gyrus LTP (Aim 2A) and putative deficits in activity-dependent potentiation of glutamate levels in dentate gyrus (Aim 2B). The milestone objective of Aim 2 will be to demonstrate the amelioration of these neurophysiological deficits as the mechanistic cornerstone of a preclinical rationale for advancing H3 receptor inverse agonists to clinical trial. Assuming we achieve the preclinical milestones, we will submit a one-year request for funding to develop a clinical trial plan. A tentative draft of plans has been developed by our clinical investigator team. First, a Phase Ib trial is proposed using three drug doses in adolescents with FASD. In addition to acquiring pharmacokinetic and safety profile data, the primary Phase Ib milestone objective will be to identify the highest safe dose of the agent producing significant improvements in combined behavioral and neurophysiologic responses, as measured using hdEEG/magnetoencephalography. Subsequently, in a Phase IIa clinical trial, we would assess the therapeutic efficacy of the optimal drug dose using a double-blind crossover design that employs the same pharmacodynamic assessments used in the Phase Ib trial. Assuming these UH3 milestones are achieved, we anticipate a subsequent, more extensive trial to assess drug efficacy in a multisite clinical trial.